Note that venetoclax, a selective inhibitor of the protein BCL-2, is approved for small subgroups of CLL patients, but the present global trial assessed the safety and efficacy in a broad patient population.

In the phase III MURANO trial, 84.9% of patients treated with venetoclax/rituximab had not progressed after 2 years compared with 36.3% of patients treated with the standard bendamustine/rituximab regimen, said John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center and Royal Melbourne Hospital in Australia.

After 23.8 months of follow-up, the median progression-free survival time for patients on the venetoclax therapy has not been reached, while the median progression-free survival for patients taking bendamustine was 17 months (P<0.0001), he said at the American Society of Hematology meeting here.

He reported that of 194 patients treated with venetoclax/rituximab, there were 32 events – either progression of disease or death, while among the 195 patients on standard bendamustine/rituximab treatment there were 114 events. He illustrated that the change in outcome was evident at one year, at which point 92.7% of the the patients taking venetoclax/rituximab had achieved progression-free survival compared with 72.5% of those on the chemotherapy based treatment.

"This is the first randomized trial comparing any of the new agents targeted to treat chronic lymphocytic leukemia against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach," Seymour reported.

In the phase III trial, researchers enrolled adult patients who had gone through 1 to 3 previous lines of therapy for chronic lymphocytic leukemia, including at least one chemotherapy regimen. If they had taken bendamustine previously they were eligible for the study if the bendamustine use was at least 2 years in the rear view mirror.

Rituximab was dosed at a rate of 375 mg/m2 on day 1 of cycle 1, and then at a dose of 500 mg/m2 on day 1 or cycles 2-6. Venetoclax was dosed at 400 mg a day orally until disease progression or intolerable toxicity for a maximum of 2 years. Bendamustine was administered at a dose of 70 mg/m2 and day 1 and 2 of each of the 6 cycles.

Leukemia cells survive an abnormally long time by producing proteins that interfere with the normal process of cell death, the researchers reported. Venetoclax is designed to hasten the death of leukemia cells by binding to and blocking the activity of one such protein, known as BCL-2. By contrast, bendamustine works by interfering with cancer cells' DNA. Rituximab is a monoclonal antibody that helps the body's immune system recognize and attack leukemia cells.

Venetoclax is approved for use against chronic lymphocytic leukemia in the U.S. and several other countries, but approvals are limited to small subgroups of patients, such as those with a specific genetic abnormality. The present trial, carried out at 109 sites globally, sought to assess the safety and efficacy of venetoclax in a broad patient population.

The patients in the study were about 65 years old, and about 40% of them had taken more than one line of treatment before becoming enrolled in the MURANO trial.

After 18 months, about 60% of the patients on venetoclax had achieved a negative assay for minimal residual disease compared with about 5% of patients treated with the bendamustine combination, Seymour said.

Overall survival was 91.9% of patients on venetoclax at 2 years compared with 86.6% for patients on bendamustine. In neither arm has the median overall survival figure been reached, he said.

The improvement in progression-free survival and overall survival did not come with a major cost in terms of adverse events. The adverse events were similar for all events, for serious adverse events, for Grade 3 and Grade 4 adverse events. There were 10 deaths among the venetoclax patients; 11 among the bendamustine patients, Seymour reported.

"These findings suggest that venetoclax should replace chemotherapy for relapsed/refractory chronic lymphocytic leukemia and is suggestive that the combination with rituximab is the preferred manner to use the drug," he said. "There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting."

In commenting on the study, press conference moderator Robert Brodsky, MD, of Johns Hopkins, predicted the MURANO results with have an immediate impact. "I think this is practice changing," he told MedPage Today.

"We are getting away from chemotherapy in chronic lymphocytic leukemia," Brodsky said. "No longer are we going to be giving drugs like bendamustine or chlorambucil because a lot of these drugs led to secondary leukemias. The goal right now is to give the least toxic ones. You will probably still see multiple regimens going forward as people avoid the alkylating agents in these treatments."

This study was supported by Genentech, a member of the Roche Group, and AbbVie.

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